The present invention relates to new nucleotide analogues. Particularly, it is concerned with the novel substituted nucleotide compounds having pharmacological activity in the treatment of viral infections in mammals.
Infections from retroviruses and related viruses are a serious cause of disease, most notably, the acquired immunodeficiency syndrome (AIDS) and Hepatitis B virus infections. The human immunodeficiency virus (HIV) has been recognized as the etiologic agent of AIDS. Compounds having an inhibitory effect on viral multiplication or are otherwise effective in the therapy of retroviral infections are being actively sought.
HBV, while classified as a hepadnavirus rather than a retrovirus, is related to retroviruses. HBV uses a reverse transcriptase enzyme for replication, like retroviruses.
Nucleoside analogues and derivatives are an important class of therapeutic agents. For example, a number of nucleoside analogues have shown antiviral activity against retroviruses (and related viruses) such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV) (PCT publication WO 89/04662 and European Patent publication 0349242 A2). Among the nucleoside analogues shown to have antiviral activity are 3xe2x80x2-azido-3xe2x80x2-deoxythymidine (AZT), 2xe2x80x2,3xe2x80x2-dideoxy-cytidine (ddC) and 2xe2x80x2-deoxy-3xe2x80x2-thiacytidine [(xe2x88x92)2-hydroxymethyl-5-(cytosin-1xe2x80x2-yl)-1,3-oxathiolane (3TC)], (European Patent publication 0382526 A2).
It is known that before nucleoside analogues can be incorporated into viral DNA, these analogues first undergo a phosphorylation step to form the triphosphorylated molecule (Jones, R. J. and Bischofbergern, N. (1995) Antiviral Res. 27:1). This is accomplished by the cell which subjects the analogue to three phosphorylations steps, the first step being rate limiting. Therefore, it is believed that, in many cases, a monophosphorylated nucleotide analogue will be incorporated with greater ease than the corresponding non-phosphorylated analogue.
Since their discovery in 1986, acyclic phosphonate nucleotide analogs have generated considerable attention as broad spectrum antiviral agents. The guanine analogues HPMPG and PMEG, the adenine analogue HPMPA, and the cytosine analogue HPMPC have been shown to exhibit good activity against human cytomegalovirus (HCMV) and herpes simplex virus (HSV). The adenine analogue PMEA has also demonstrated in vitro activity against retroviruses such as the human immunodeficiency virus (HIV), as well as DNA viruses such as HSV, and in vivo activity against murine cytomegalovirus (CMV). 
Unfortunately, these compounds present problems due to their cytotoxicity, particularly, PMEG is very cytotoxic. Cyclic phosphonate nucleotides related to HPMPA have been synthesized but exhibited little or no antiviral activity (Collect. Chez. Chem. Commun. (1993) 58: 2159-2191).: These compounds have been reported to exhibit little or no activity against some DNA viruses and no activity against retroviruses and RNA viruses.
In order to facilitate the uptake of the phosphorylated nucleotide analogues and increase their bioavailability, several neutral monophosphorylated nucleotide prodrugs have been developed. These neutral nucleotides are more lipophilic due to the masking of the negative charge of the phosphate group with enzyme or pH labile neutral substitutes. This allows the prodrug to penetrate the cell membrane much more readily than their corresponding 5xe2x80x2-monophosphate dianion counterpart. Once inside the cell, the prodrug decomposes to generate the original monophosphorylated nucleotide analogue which can then be further phophorylated and incorporated into the viral DNA. To achieve this result several substituents have been developed for use in the preparation of monophosphorylated nucleotide prodrugs. Examples of these substituents include S-acyl-2-thioethyls (SATE) (J. Med. Chem. (1995) 38:3941-3950, Antiviral Chem. Chemother. (1998) 9(1):41-52.) such as methyl (SATE), isopropyl(SATE), t-butyl(SATE) and phenyl(SATE), or carboxyloxymethyl such as pivaloyloxymethyl (POM) (Antiviral Chem. Chemother (1994) 5:91-98) and di-S-[(2-hydroxyethyl)sulfidyl]-2-thioethyl. Additionally, substituents such as alkyl methyl carbonates, for example isopropyl methyl carbonate (POC), have also been used to form alkylmethyl carbamate prodrugs (Antiviral Chem. Chemother. (1997) 8: 557-564). Recently, an alternative approach has been developed by the synthesis of phenyl and benzylphosphotriesters analogues (Bioorg. Med. Chem. Lett. (1997) 7: 99-104) and phophostriesters analogues (WO98/17281) of nucleotides have been prepared exhibiting antiviral activity.
The present invention relates to novel nucleotide analogues having the general formula (I): 
and pharmaceutically acceptable derivatives thereof, for example, pharmaceutically acceptable salts, esters, or salts of such esters, wherein
n is 0 or 1;
X is O, S, CH2, CH-halogen, CHxe2x80x94N3, or Cxe2x95x90CH2;
Q and U are independently selected from S, O, CF2, Cxe2x95x90CH2. CH(Ra) or U and Q are both CH and Q and U are linked by a double bond;
Ra is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb, NHRb, or SRb;
Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl, C1-6 acyl, or C(O)ORc;
Rc is C1-6 alkyl or C1-6 acyl;
Z is (CH2)m wherein m is 1;
R1 and R1xe2x80x2 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C7-11 arylmethyl, C2-7 acyloxymethyl, C3-8 alkoxycarbonyloxymethyl, C7-11 aryloyloxymethyl, C3-8 S-acyl-2-thioethyl, phosphate or diphosphate;
R2 is a purine or pyrimidine base or a derivative thereof, provided that when R2 is adenine, Ra is CN, halogen, N3, NH2, SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb, NHRb, SRb wherein Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl.
The present invention also includes methods and compositions for the treatment of viral infections in mammals. Particularly, methods and compositions for the treatment of infections by retroviruses and related viruses. Of special interest are methods and compositions for the treatment of acquired immunodeficiency syndrome (AIDS) and/or Hepatitis B virus infections in mammals.
The present inventions also includes compositions which contains mixtures of compounds of the present invention active against viral infections as well as combinations of compounds of the present invention active against viral infections and other therapeutic agents.
The present invention relates to a novel nucleotide analogue having the general formula (I): 
and pharmaceutically acceptable derivatives thereof, for example, pharmaceutically acceptable salts, esters, or salts of such esters, wherein
n is 0 or 1;
X is O, S, CH2, CH-halogen, CHxe2x80x94N3, or Cxe2x95x90CH2;
Q and U are independently selected from S, O, CF2, Cxe2x95x90CH2. CH(Ra) or U and Q are both CH and Q and U are linked by a double bond;
Ra is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb, NHRb, or SRb;
Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl, C1-6 acyl, or C(O)ORc;
Rc is C1-6 alkyl or C1-6 acyl;
Z is (CH2)m wherein m is 1;
R1 and R1xe2x80x2 are independently selected from the group H, C1-6 alkyl, C2-6 alkenyl, C6-10 aryl, C7-11 arylmethyl, C2-7 acyloxymethyl, C3-8 alkoxycarbonyloxymethyl, C7-11 aryloyloxymethyl, C3-8 S-acyl-2-thioethyl, phosphate or diphosphate;
R2 is a purine or pyrimidine base or derivative thereof, provided that when R2 is adenine, Ra is CN, halogen, N3, NH2, SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb, NHRb, SRb wherein Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl.
The compounds of the present invention may be in the form of single enantiomers having a xcex1-D, xcex1-L, xcex2-D , xcex2-L, R or S configuration at each chiral center, or a mixture thereof, e.g., a racemic mixture.
The present invention additionally includes the use of compounds of formula (I) in the treatment of viral infections in mammals. Particularly, the invention includes the use of the nucleotides of formula (I) in the treatment of viral infections caused by the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV) in mammals. The compounds of the present invention may be used alone or in combination with one or more therapeutic agents in the treatment of a viral infection.
Additionally, the invention includes the use of the nucleotides of this invention in the preparation of antiviral formulations or the preparation of a medicament for viral infections.
The invention relates to a novel class of phosphonate nucleotide analogues having the general formula (I) and pharmaceutically acceptable derivatives thereof. Members of this series of analogues possess anti-viral activity against retroviruses, such as HIV, and related viruses, such as HBV.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of C1-30, particularly C1-6, unsubstituted or optionally mono- or di-substituted by hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), C6-12 aryl, C2-12 alkoxyalkyl or nitro. It specifically includes methyl, ethyl, cyclopropyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
The term xe2x80x9cacylxe2x80x9d, as used hereinafter, refers to a radical derived from an aliphatic carboxylic acid, by removal of the xe2x80x94OH group of 1 to 30 carbon atoms, particularly 1 to 6 carbon atoms. Like the acid to which it is related, an aliphatic acyl radical may be substituted (by a hydroxy, N3, CN, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro) or unsubstituted, and whatever the structure of the rest of the molecule may be, the properties of the functional group remain essentially the same (e.g., acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, butyryl, pentanoyl, 3-methylbutyryl, hydrogen succinate, mesylate, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, 3-chlorobenzoate, trifluoroacetyl, chloroacetyl, and cyclohexanoyl).
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d represent substituted (by NH2, SH, N3, CN, halogen, hydroxyl or C6-20 aryl) or unsubstituted straight, branched or cyclic hydrocarbon chains having 2 to 30 carbon atoms and preferably from 2 to 6 carbon atoms and containing at least one unsaturated group (e.g. allyl, vinyl ).
The term xe2x80x9calkoxyxe2x80x9d represents a substituted (by hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), C6-12 aryl, C2-12 alkoxyalkyl or nitro) or unsubstituted alkyl group containing from 1 to 30 carbon atoms and preferably from 1 to 6 carbon atoms, wherein the alkyl group is covalently bonded through an oxygen atom (e.g., methoxy and ethoxy). The substituents include those listed above in the description of alkyl groups.
The term xe2x80x9carylxe2x80x9d represents a aromatic moiety which may be unsubstituted or substituted by hydroxy, N3, CN, halogen (F, Cl, Br, I), SH, amino, trifluoromethyl, C1-6 alkyl, C1-5 alkoxy, C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro, and containing at least one benzenoid-type ring. The group may contain from 6 to 14 carbon atoms (e.g., phenyl and naphthyl), particularly 6 to 10 carbon atoms.
The term xe2x80x9caryloxyxe2x80x9d represents a substituted (as described above for aryl, e.g., by a halogen, trifluoromethyl or C1-5 alkoxy) or unsubstituted aryl moiety, having 6 to 14 carbon atoms, covalently bonded through an oxygen atom (e.g., benzyloxy, phenoxy).
The term xe2x80x9carylalkylxe2x80x9d or xe2x80x9caralkylxe2x80x9d represents a substituent comprising an aryl moiety attached via an alkyl chain (e.g. benzyl, phenylethyl) wherein the sum total of carbon atoms for the aryl moiety and the alkyl chain is 7 to 21. The aryl portion or alkyl chain portion of the group are unsubstituted or optionally mono- or di-substituted with OH, SH, amino, or halogen. The aryl portion can also be substituted as described above for aryl, e.g., by C1-6 alkyl.
The term xe2x80x9cthiolxe2x80x9d represents C1-6 alkyl, C6-15 aryl, C7-21 aralkyl, C2-6 alkenyl or C2-6 alkynyl groups covalently bonded to an adjacent sulfur atom bearing a hydrogen.
The term xe2x80x9calkylthioxe2x80x9d (e.g. thiomethy, thioethyl) refers to C1-6 alkyl, unsubstituted or optionally mono- or di-substituted by hydroxy, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro, covalently bonded to an adjacent sulfur atom.
The term xe2x80x9carylthioxe2x80x9d (e.g. thiophenyl, thiobenzyl), refers to C6-10 aryl groups, unsubstituted or optionally mono- or di-substituted by substituents as described above for aryl, e.g., hydroxy, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro, covalently bonded to an adjacent sulfur atom.
The term xe2x80x9cacyloxyxe2x80x9d refers to an acyl group having a 1 to 30 carbon atom chain, particularly 1 to 6 carbon atoms, which is bonded through an oxygen atom and can be saturated or unsaturated, and straight or branched (e.g.: acetyloxy). The chain may be unsubstituted or optionally mono- or di-substituted by hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro.
The term xe2x80x9calkoxycarbonylxe2x80x9d refers to an alkoxy group having a 1 to 30 carbon atoms chain, particularly 1 to 6 carbon atoms, which can be saturated or unsaturated, straight or branched (e.g.: CH3Oxe2x80x94COxe2x80x94) that is bonded through a carbonyl group. The chains may be unsubstituted or optionally mono- or di-substituted by hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro.
The term xe2x80x9calkoxyalkylxe2x80x9d represents a C1-6 alkoxy group attached to an adjacent C1-6 alkyl group (e.g., methoxymethyl, ethoxymethyl). They may be unsubstituted or optionally mono- or di-substituted by hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C1-6 alkoxy or nitro.
The term xe2x80x9cheterocyclexe2x80x9d represents a saturated or unsaturated mono- or polycyclic (e.g. bicyclic) ring incorporating 1 or more (e.g.:1-4) heteroatoms selected from N, O and S. It is understood that a heterocycle is optionally mono- or di-substituted with OH, SH, halogen, CF3, oxo or C1-6 alkyl. Examples of suitable monocyclic heterocycles include but are not limited to pyridine, piperidine, pyrazine, piperazine, triazine, pyrimidine, imidazole, thiazole, oxazole, furan, thiofuran, pyran and thiophene. Examples of suitable bicyclic heterocycles include but are not limited to indole, benzimidazole, quinoline, isoquinoline, purine, and carbazole.
The term xe2x80x9caminoxe2x80x9d represents NH2 or an amino substituted by one or two C1-6 alkyl, C6-10 aryl, C2-6 alkenyl, C2-6 alkynyl, or C7-12 aralkyl groups, which groups are unsubstituted or optionally mono- or di-substituted by hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), C6-12 aryl, C1-6 alkyl, C2-12 alkoxyalkyl or nitro, wherein the carbon atoms are covalently bonded to an adjacent element through a nitrogen atom (e.g. pyrrolidine). They include primary, secondary and tertiary amines and quaternary ammonium salts.
It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least two chiral centers (shown as * in formula (I)) and thus exist in the form of two pairs of optical isomers (i.e. enantiomers) and mixtures thereof including racemic mixtures. Thus the compounds of formula (I) may be either cis isomers, as represented by formula (IA), or trans isomers, as represented by formula (IB), or mixtures thereof. Each of the cis and trans isomers can exist as one of two enantiomers, R or S at each chiral center, or as mixtures thereof including racemic mixtures. Depending on the substitution of U or Q compounds of the present inventions may have a third and/or fourth chiral center. The position of the substituents in these chiral centers will have an effect on the antiviral characteristics of the compound object of the present invention. All such isomers and mixtures thereof including racemic mixtures are included within the scope of the invention. 
By purine or pyrimidine base derivative is meant a naturally occurring purine or pyrimidine base which mimics such bases in that their structures (the kinds of atoms and their arrangement) are similar to the normal bases but may possess additional or lack certain of the functional properties of the normal bases. Derivatives of such bases or analogues include those obtained by replacement of a CH moiety by a nitrogen atom (for example, 5-azapyrimidines such as 5-azacytosine) or vice versa (for example 7-deazapurines, such as 7-deazadenine or 7-deazaguanine) or both (e.g. 7-deaza, 8-azapurines) or may have ring substituted by halogen, hydroxyl, azido, cyano, amino, substituted amino, thiol, C1-6 alkyl and C6-10 aryl.
By the term xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d of a compound is meant any pharmaceutically acceptable salt, ester, or salt of such ester of a compound of formula (I), or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) a compound of formula (I) or an antivirally active metabolite or residue thereof. It will be appreciated by those skilled in the art that the compounds of formula (I) may be modified to provide pharmaceutically acceptable derivatives thereof, at functional groups in the base moiety. Modifications at all such functional groups are included within the scope of the invention.
Conveniently, the group R2 is selected from: 
wherein:
x is oxygen, NH or sulfur.
y is oxygen, NH or sulfur.
R3 and R4 are independently selected from hydrogen, hydroxyl, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-10 acyl, C6-10 aryl, C6-11 arylcarbonyl, C2-7 alkoxycarbonyl, C6-11 aryloxycarbonyl, C2-7 alkylaminocarbonyl, or amino acids.
R3 may be a saturated or unsaturated C3-8 carbocyclic ring optionally substituted with COOH, C(O)NH2, OH, SH, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C(O)R13 wherein R13 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C(O)OR14 wherein R14 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl; and R4 is chosen from H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
R3R4 can also be connected to the nitrogen atom to form a saturated or unsaturated C3-8 heterocyclic ring optionally substituted with C(O)OH, C(O)NH2, OH, SH, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C(O)R13 wherein R13 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C(O)OR14 wherein R14 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl.
R5, R6, R11, and R12 are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, carbamoyl, C2-7 alkoxycarbonyl, hydroxymethyl, trifluoromethyl, C6-10 arylthio which is unsubstituted or substituted by, e.g., halogen or azido, C1-6 alkyl which is unsubstituted or substituted by, e.g., halogen or azido, C2-6 alkenyl which is unsubstituted or substituted by, e.g., halogen or azido, C2-6 alkynyl which is unsubstituted or substituted by, e.g., halogen or azido, C1-6 acyloxy, thiocarboxy, thiocarbamoyl, carbamate, ureido, amidino, or C6-10 aryloxy.
Alternatively, Group R2 is selected from: 
wherein:
R7, R8, R9, and R10 are each independently selected from the group is chosen from hydrogen, hydroxy, C1-6 alkoxy, thiol, C1-6 alkylthio, amino, amino substituted by, for example, a structure in accordance with formulas (II)-(IV), halogen, azido, cyano, carboxyl, C2-7 alkoxycarbonyl, carbamoyl, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, C1-6 acyloxy, C6-10 aryl, C6-10 aryloxy, C1-6 thiocarboxy, thiocarbamoyl, carbamate, ureido, amidino, C6-10 aryloyloxy or -NR19R20 wherein:
R19 is H, a saturated or unsaturated C3-6 carbocyclic ring optionally substituted with COOH, C(O)NH2, OH, SH, NH2, NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C1-6 acyl, C6-10 aryl, C(O)R21 wherein R21 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or COOR22 wherein R22 is C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl; and R20 is chosen from H, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl.
R19R20 can also be connected to the nitrogen atom to form a saturated or unsaturated C3-6 heterocyclic ring optionally substituted with COOH, C(O)NH2, OH, SH, NH2, NO2, C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C(O)R21 wherein R21 is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or COOR22 wherein R22 is a C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl.
In an alternative embodiment of the present invention R7 is represented by H, F, I, Br, Cl, NH2, OH or the formula 
wherein
q is an integer selected from 1 to 4
R18 is selected from the group comprising H, COOH, C(O)NH2, OH, SH, NH2, NO2, N3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C(O)Rd wherein Rd is a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C(O)ORe wherein Re is C1-6 alkyl or C2-6 alkenyl, C2-6 alkynyl; and
R17 is H or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl.
In an alternative embodiment, q is 1 or 2, R17 is H or methyl, and R18 is H, C(O)OH, C(O)NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl and C(O)ORd wherein Rd is C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl.
In an alternate embodiment of the present invention, q is 1, R17 is H and R18 is H, COOH, or C1-6 alkyl.
In an additional embodiment of the present invention R18 is H, COOH, methyl or ethyl.
In an additional embodiment of the present invention R18 is methyl or ethyl.
In an additional embodiment of the present invention, R18 is COOH.
In an additional embodiment of the present invention R18 is H.
In an additional embodiment of the present invention, R17 is H or methyl and R18 is H.
In an additional embodiment of the present invention R18 and R17 are H.
In an alternate embodiment R8, R9, and R10 are each independently chosen from hydrogen, hydroxy, amino, substituted amino, halogen, azido or methyl.
The compounds of the present invention include those wherein R7 is Cl, hydroxyl, NH2 or the formula 
wherein
q is an integer selected from 1 or 2;
R18 is selected from H or C(O)OH;
R8, R9, R10 and R17 are hydrogen; and
R5 is F, I, Cl, or CH3.
In another embodiment of the present invention, R2 is chosen from formulas: 
Wherein
R3, R4, and R6 are H;
R5 is H, F, Cl, I, Br, hydroxyl or amino;
x and y are O or S;
R7 is H, F, Cl, I, Br, hydroxyl, amino or the formula 
xe2x80x83wherein:
q is an integer selected from 1 or 2;
R17 is H or methyl;
R18 is H, COOH, or C1-6 alkyl;
and R8 and R9 are each independently chosen from hydrogen, hydroxyl, amino, substituted amino, halogen, azido or methyl.
Additionally the present invention includes compound wherein R2 is selected from cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine; 2-amino-6-[1-carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine.
The purine or pyrimidine base R2 is linked through the linker xe2x80x9cZxe2x80x9d at any position on the base, but preferably at N9- for the purines, or N1- or N3-position for the pyrimidines.
In an alternate embodiment of the present invention compounds of formula (I) are in the cis configuration.
In an alternate embodiment of the present invention, compounds of formula (I) have both Z(R2) and (CH2)nP(O)O2R1R1xe2x80x2 are both in either the R or S configuration.
In an alternate embodiment of the present invention, compounds of formula (I) have Z(R2) and (CH2 )nP(O)O2R1R1xe2x80x2 in the cis configuration. In an additional embodiment, compounds of formula (I) have Z(R2), (CH2)nP(O)O2R1R1xe2x80x2 and Ra in the cis configuration.
In an alternative embodiment of the present invention the following elements of the compounds of formula (I) are chosen:
X is O;
Q is CH2;
U is chosen from: Cxe2x95x90CH2 or CH(Ra) wherein Ra is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl which is unsubstituted or substituted by OH, F, I Cl, Br, NH2 or SH, C2-6 alkenyl which is unsubstituted or substituted by OH, F, I Cl, Br, NH2 or SH, C2-6 alkynyl which is unsubstituted or substituted by OH, F, I Cl, Br, NH2 or SH, C(O) Rb, NHRb or SRb wherein Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl ,C1-6 acyl, or C(O)ORC wherein RC is C1-6 alkyl;
Z is (CH2)m wherein m is 1;
R1 and R1xe2x80x2 are independently selected from hydrogen, C2-7 acyloxymethyl, C3-8 alkoxycarbonyloxymethyl, phenyl, benzyl, C3-8 S-acyl-2-thioethyl, phosphate or diphosphate;
R2 is chosen from formulas (A), (B), (C), (D), (E), (F), (G), (H), (L) and (M), (N), (O), (P), (R), (S), (T) wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, and R12 are defined herein above, provided that when R2 is adenine, Ra is CN, halogen, N3, NH2, SH, C1-6 alkyl which is unsubstituted or substituted by OH, F, I Cl, Br, NH2 or SH, C1-6 alkenyl which is unsubstituted or substituted by OH, F, I Cl, Br, NH2 or SH, C2-6 alkynyl which is unsubstituted or substituted by OH, F, I Cl, Br, NH2 or SH, C(O)Rb, NHRb, SRb wherein Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl
In an optional embodiment of the present invention, the compounds of formula (I) are in the cis configuration and
X is O;
Q is either CH2 or CH;
U is CH(Ra) wherein Ra is chosen from hydrogen, OH, CN, F, Cl, I, Br, N3, NH2, SH, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb, NHRb, SRb wherein Rb is hydrogen, OH, CN, halogen, N3, NH2, SH, C1-6 alkyl or Cl6 acyl, C(O)ORC wherein Rc is C1-6 alkyl or C1-6 acyl, or U is CH provided that Q is CH and Q and U are linked by a double bond;
Z is (CH2)m wherein m is 1;
R1 and R1xe2x80x2 are each independently chosen from hydrogen, phosphate or diphosphate; and
R2 is chosen from formulas: 
xe2x80x83Wherein
R3, R4, and R6 are H;
R5 is H, F, Cl, I, Br, hydroxyl or amino;
x and y are independently selected from O or S;
R7 is H, F. Cl, I, Br, hydroxyl, amino or the formula 
xe2x80x83wherein:
q is an integer selected from 1 or 2;
R17 is H or methyl;
R18 is H, COOH, or C1-6 alkyl;
and R8 and R9 are each independently chosen from hydrogen, hydroxyl, amino, substituted amino, halogen, azido or methyl.
In an alternative embodiment the compounds of formula (I) of the present invention are in the cis configuration and are chosen from those wherein
X is O;
U is Cxe2x95x90CH2, CHxe2x80x94OH, CHxe2x80x94F, CHxe2x80x94Cl, CHxe2x80x94Br, CHxe2x80x94I or CHxe2x80x94N3;
Q is CH2;
Z is (CH2)m wherein m is 1;
R1 and R1xe2x80x2 are hydrogen, phosphate or diphosphate; and
R2 is chosen from formulas: 
xe2x80x83Wherein
R3, R4, R6 and R9 are H;
R5 is H, F, Cl, I, Br, hydroxyl, methyl or amino;
x and y are O or S;
R7 is H, F, Cl, I, Br, hydroxyl, amino or the formula: 
xe2x80x83wherein:
q is an integer selected from 1 or 2;
R17 is H or methyl;
R18 is H, COOH, or C1-6 alkyl;
and R8 is amino, provided that when R2 is adenine, U is Cxe2x95x90CH2, CHxe2x80x94F, CHxe2x80x94Cl, CHxe2x80x94Br, CHxe2x80x94l, Cxe2x80x94NH2 or CHxe2x80x94N3.
Alternatively, an embodiment of the present invention is represented by compounds of formula (I) wherein:
X is O;
Q is CH2;
U is chosen from CH2, Cxe2x95x90CH2, CHxe2x80x94OH, CHxe2x80x94F, CHxe2x80x94Cl, CHxe2x80x94Br, CHxe2x80x94I, Cxe2x80x94NH2 or CHxe2x80x94N3;
Z is (CH2)m wherein m is 1;
R1 and R1xe2x80x2 are hydrogen, phosphate or diphosphate;
R2 is cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine; 2-amino-6-[1-carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine, provided that when R2 is adenine, U is Cxe2x95x90CH2, CHxe2x80x94F, CHxe2x80x94Cl, CHxe2x80x94Br, CHxe2x80x94I, Cxe2x80x94NH2 or CHxe2x80x94N3.
Pharmaceutically acceptable salts of the compounds of formula (I) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, p-toluenesulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphtalene-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and N(Rxe2x80x2)4+ (where Rxe2x80x2 is C1-4 alkyl) salts.
References hereinafter to a compound according to the invention includes both the compound of formula (I) and its pharmaceutically acceptable derivatives.
Compounds of formula (I) include: 
Wherein:
R2 is cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine; 2-amino-6-[1-carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine; and
Ra is H, OH, CN, F, Cl, Br, I, NH2 or N3, provided that when R2 is adenine, Ra is CN, F, Cl, Br, I, N3 or NH2.
In an alternative embodiment of the present invention, compounds of formula (I) are selected for formulas (i), (iv), (vii), (viii), (x), (xii), (xiii), or (xvi), wherein R2 is chosen from cytosine, adenine, guanine, uracil, thymine, 2-amino-6-chloropurine, 6-chloropurine, 2,6-diaminopurine, 2-amino-6-cyclopropylamino-purine; 2-amino-6-[1-carboxylic acid-cyclopropylamino]-purine, 2-amino-6-cyclobutylamino-purine, 2-amino-6-azetidino-purine, 2-amino-6-cyclopentylamino-purine or 5-fluoropyrimidine; and
Ra is OH, F, Cl, Br, I or N3, provided that when R2 is adenine Ra is F, Cl, Br, I or N3.
Specific compounds of formula (I) include:
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-ami no-6-hyd roxy-purin-9-ylmethyl)-(4S)-hyd roxy-tetrahyd ro-fu ran-(2S)-phosphonate
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2R)-phosphonate
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2R)-phosphonate
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2S)-phosphonate
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-chloro-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-chloro-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-hydroxy-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2R)-phosphonate.
[(5R)-2(2-amino-6-hydroxy-purin-9-ylmethyl)4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid.
[(5S)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2S)-20 yl]-phosphonic acid.
[(5R)-2(2-amino-6-hydroxy-purin-9-ylmethyl)4-methylene-tetrahydro-furan(2S)-yl]-phosphonic acid.
[(5S)-2(2-amino-6-hydroxy-purin-9-ylmethyl)4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid.
[(5R)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-2,5-dihydro-furan-(2R)-yl]-phosphonic acid;
[(5S)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-2,5-dihydro-furan-(2S)-yl]-phosphonic acid;
[(5R)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-2,5-dihydro-furan-(2S)-yl]-phosphonic acid;
[(5S)-2(2-amino-6-hydroxy-purin-9-ylmethyl)-2,5-dihydro-furan-(2R)-yl]-phosphonic acid;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-tetrahydro-furan-(2S)-phosphonate.
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-tetrahydro-furan-(2R)-phosphonate.
(5S)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-tetrahydro-furan-(2S)-phosphonate.
(5S)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-tetrahydro-furan-(2R)-phosphonate.
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-azido-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-azido-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-fluoro-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-fluoro-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-hydroxy-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-hydroxy-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-iodo-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-iodo-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-yl methyl)-(4R)-chloro-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl )-(4R)-chloro-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-yl methyl)-(4S)-chloro-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-chloro-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4R)-bromo-tetrahydro-furan-(2R)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2S)-phosphonate;
(5R)-(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4S)-bromo-tetrahydro-furan-(2R)-phosphonate;
[(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-(4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid;
[(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2S)-yl]-phosphonic acid;
[(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)4-methylene-tetrahydro-furan(2S)-yl]-phosphonic acid;
[(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-4-methylene-tetrahydro-furan(2R)-yl]-phosphonic acid;
[(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2R)-yl]-phosphonic acid;
[(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2S)-yl]-phosphonic acid;
[(5R)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2S)-yl]-phosphonic acid;
[(5S)-2(2-amino-6-cyclopropylamino-purin-9-ylmethyl)-2,5-dihydro-furan-(2R)-yl]-phosphonic acid;
The compounds of formula (I) and of formulas i to xii, either as an isononic mixture or as the individual enantiomer; and useful for the treatment of humans or mammalians to inhibit at least one of the following viruses: HCMV (Human Cytomegalovirus), HSV-1 or HSV-2 (Herpes Simplex 1 or 2), HIV (Human Immunodeficiency Virus), HTLV (Human T-lymphotropic virus), or HBV (Hepatitis B Virus). In a specific embodiment of the present invention compounds of formula (I) are active against HIV (Human Immunodeficiency Virus) and HBV (Hepatitis B Virus).
In a further aspect of the present invention, there is provided a method for the treatment of a viral infection in an infected host comprising the step of administering an antivirally effective dose of a compound of formula (I) as defined herein above or a pharmaceutically acceptable derivative thereof. In an alternative embodiment of the present invention the host is a mammal.
As will be appreciated by those skilled in the art, the compounds in accordance with the invention can be used for prophylaxis as well as the treatment of established infections of symptoms.
The compounds of the present invention may also be useful in the treatment of AIDS-related conditions such as AIDS-related complex (ARC), persistent generalized lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia), anti-HIV antibody-positive and HIV-positive conditions, Kaposi""s sarcoma, thrombocytopenia purpura and opportunistic infections.
The compounds of the invention are also useful in the prevention or progression to clinical illness of individuals who are anti-HIV antibody or HIV-antigen positive and in prophylaxis following exposure to HIV.
The compounds of formula (I) or the pharmaceutically acceptable salts and esters thereof, may also be used for the prevention of viral contamination of biological fluids such as blood or semen in vitro.
The present invention also includes a commercial package containing one or more compounds of formula (I) or the pharmaceutically acceptable salts or esters thereof as an active agent with instructions of use as treatment against antiviral infections in mammals.
It will also be appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of body weight per day, preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20 mg/kg/day.
The desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
The compound is conveniently administered in unit dosage form; for example containing 10 to 1500 mg, conveniently 20 to 1000 mg, most conveniently 50 to 700 mg of active ingredient per unit dosage form.
Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 1 to about 75 xcexcM, preferably about 2 to 50 xcexcM, most preferable about 3 to about 30 xcexcM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1 to about 100 mg of the active ingredient. Desirable blood levels may be maintained by a continuous infusion to provide about 0.01 to about 5.0 mg/kg/hour or by intermittent infusions containing about 0.4 to about 15 mg/kg of the active ingredient.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulation suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
The compounds of formula (I) according to the invention may also be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing an/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
For topical administration to the epidermis, the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
Formulations suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
For intra-nasal administration the compounds of the invention may be used as a liquid spray or dispersible powder or in the form of drops. Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.
For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges or, e.g., gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
When desired the above described formulations adapted to give sustained release of the active ingredient may be employed.
The pharmaceutical compositions according to the invention may also contain other active ingredients such as antimicrobial, antifungal, and antiviral agents, immunomodulators or preservatives.
The compounds of the invention may also be used in combination with other therapeutic or prophylactic agents for example other antiinfective agents. In particular the compounds of the invention may be employed together with known antiviral, antimicrobial, or antifungal agents or immunomodulators. The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or) or a pharmaceutically acceptable derivative thereof together with another therapeutically active agent, in particular, an antiviral agent.
The therapeutically active agent to be used in combination with the compounds of the present invention may be selected from the group epivir, DAPD, FTC, AZT, d4T, nevirapine, DMP-226, nelfinavir, indinavir, delavirdine, MKC-442, 1592U89 (abacavir), 141W94, MK-639, saquinavir, ritonavir ,TIBO, HEPT, BHAP, xcex1-APA, TSAO, calanolides, L-697,661, 2xe2x80x2,3xe2x80x2-dideoxycytidine (ddC), 2xe2x80x2,3xe2x80x2-dideoxyadenosine, 2xe2x80x2,3xe2x80x2-dideoxyinosine (ddI), 3xe2x80x2-deoxythymidine, 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydro-thymidine, and 2xe2x80x2,3xe2x80x2-dideoxy-2xe2x80x2,3xe2x80x2-didehydrocytidine and ribavirin; acyclic nucleosides such as acyclovir, ganciclovir, interferons such as alpha-, beta-and gamma-interferon; glucuronation inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, ampligen, thymomodulin, thymopentin, foscarnet, glycosylation inhibitors such as 2-deoxy-D-glucose, castanospermine, 1-deoxynojirimycin; and inhibitors of HIV binding to CD4 receptors such as soluble CD4, CD4 fragments, CD4-hybrid molecules and inhibitors of the HIV aspartyl protease such as L-735,524.
In accordance with a further aspect of the present invention, the further therapeutic agent or agents may be chosen from epivir, DAPD, FTC, AZT, nevirapine, DMP-226, nelfinavir, indinavir, delavirdine, MKC-442, abacavir, 141W94, MK-639, saquinavir, ritonavir, acyclovir, interferon alfa, L-735,524, d4T, ddC, and ddI.
The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention.
In another aspect method of treating a host infected with an HIV strain which includes administering an effective dose of a compound or the combinations of compounds of formula (I) capable of inhibiting viral replication.
When the compound of formula (I) or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may be either the same or differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
The advantageous effects of the compounds of formula (I) and the second antiviral agents are observed over a wide ratio for example 1:250 to 250:1, alternatively 1:50 to 50: 1, particularly about 1 :10 to 10:1. Conveniently each compound will be employed in the combination in an amount at which it exhibits antiviral activity when used alone.
In an embodiment of the present invention the infected host is a mammal. Alternately, the infected host is human.
It is expected that the present combinations will be generally useful against viral infections or virus-associated tumours in humans, and the method of their use to inhibit viral infectivity or tumour growth in vitro or in vivo is also within the scope of the present invention.
Thus, there is provided, as a further aspect of the invention, a method for the treatment of a viral infection in a mammal, including man, comprising co-administration of an antiviral compound of formula (I) and a further antiviral report which inhibits HIV or HBV replication. Therapeutic methods comprising administration of a combination of a compound of formula (I) and more than one of the second antiviral agents, either together or in a plurality of paired combinations, is also within the scope of the invention.
It will be appreciated that the compound of formula (I) and the second antiviral agent may be administered either simultaneously, sequentially or in combination. If administration is sequential, the delay in administering the second of the active ingredients should not be such as to lose the benefit of the synergistic effect of the combination. Preferably administration will be simultaneous.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
It will be further appreciated that the amount of a combination of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 1 to about 750 mg/kg e.g. from about 10 to about 75-mg/kg of bodyweight per day, such as 3 to about 120 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day of each of the active ingredients of the combination.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
The compounds of formula (I) may be prepared by the process outlined in Scheme 1, wherein X is an oxygen, Q and U are each independently CH2, CHOH, CH-halogen, CHxe2x80x94N3, or both Q and U are CH linked by a double bond. Derivatives of compounds of formula (I) may be prepared by following procedures outlined in the literature, e.g.:S-acyl-2-thioethyl (SATE) in J. Med. Chem. (1995) 38:3941-3950; carboxyloxymethyl such as pivaloyloxymethyl (POM) in Antiviral Chem. Chemother (1994) 5:91-98 or alkyl methyl carbonates, such as isopropyl methyl carbonate (POC) in Antiviral Chem. Chemother. (1997) 8: 557-564; phenyl or benzylphosphotriesters analogues in Bioorg. Med. Chem. Lett. (1997) 7: 99-104 or phosphotriesters analogues in WO98/17281. 
X, U and Q are as defined herein above.
W is a displaceable group (such as acetoxy, halogen, methoxy, methoxyethyloxy, tosyloxy, mesyloxy.)
Wxe2x80x2 is a hydroxy protecting group (such as silyloxy, acyloxy, aracyloxy, trityloxy).
Wxe2x80x3 is a displaceable group (such as hydroxy, mesyloxy, tosyloxy, halogen.).
Z is (CH2)m, where m is 0 or an integer from 1-3 (preferably m=1)
n is 0 to 1 (preferably n=0)
Rv is a hydroxy protecting group such as a C1-6 alkyl or an C6-10 aryl (preferably methyl, ethyl, isopropyl,. phenyl or benzyl)
R2 is as defined above, profoundly a purine or pyrimidine (preferably attaching at N-9 position for purine and N-1 or N-3 for pyrimidine).
The steps illustrated in scheme can be briefly described as follows:
a) Both hydroxy groups of compound (A) are sequentially converted to form compound (B) where W and Wxe2x80x2 are similar or different protecting groups as defined above;
b) The W functionality of compound (B) is then converted to a 2-dialkylphosphonate derivative (C) under Arbuzov conditions by treatment with trialkyl phosphite with or without of a Lewis acid such as TiCl4 as a catalyst. At this stage, compound (C) may be optionally separated to its cis and trans isomers before further steps are carried out. Wxe2x80x2 is then converted to Wxe2x80x3 by deprotection to the hydroxy function. At this stage, the corresponding hydroxy derivative may be optionally used for the Mitsunobu coupling reaction with a purine or pyrimidine base or may be converted to a displaceable group as defined above.
c) Wxe2x80x3 is displaced by a purine or pyrimidine base to give compound (D).
d) Once made, ester (D) is converted to the corresponding phosphonate derivative (E).